A Phase I/II, Multiple-Dose, Dose-Escalation Study of Siltuximab, an Anti-Interleukin-6 Monoclonal Antibody, in Patients with Advanced Solid Tumors
A Phase I/II, Multiple-Dose, Dose-Escalation Study of Siltuximab, an Anti-Interleukin-6 Monoclonal Antibody, in Patients with Advanced Solid Tumors
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DOI：
10.1158/1078-0432.ccr-13-2200
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发表时间：
2014-04-15
影响因子：
11.5
通讯作者：
Kurzrock, Razelle
中科院分区：
文献类型：
--
作者：
Angevin, Eric;Tabernero, Josep;Kurzrock, Razelle
目的：这项I/II期研究评估了逐步增加的多剂量siltuximab（一种源自新的中国仓鼠卵巢（CHO）细胞系的嵌合抗白细胞介素（IL）-6单克隆抗体）在晚期/难治性实体瘤患者中的安全性、疗效和药代动力学。在I期剂量递增队列中，20例晚期/难治性实体瘤患者接受了司妥昔单抗2.8或5.5 mg/kg每2周一次或11或15 mg/kg每3周一次静脉内（i. v.）给药。在I期扩展（n = 24）和II期队列（n = 40）中，患有Kirsten大鼠肉瘤-2（KRAS）突变型肿瘤、卵巢癌、胰腺癌或抗EGF受体（EGFR）难治性/耐药非小细胞肺癌（NSCLC）、结直肠癌或H&N癌的患者每3周接受15 mg/kg。第二阶段的主要疗效终点是完全反应，部分反应，或稳定的疾病>6 wk.Results：84例患者（35结直肠癌，29卵巢癌，9胰腺癌，和11其他）接受了中位数为3（范围，1-45）周期。在5.5 mg/kg剂量下发生了一次剂量限制性毒性。常见的≥ 3级不良事件为肝功能异常（15%）、身体健康恶化（12%）和疲劳（11%）。10%的患者发生了与西妥昔单抗相关的≥ 3级不良事件。中性粒细胞增多症（4%）是在>1名患者中报告的唯一可能相关的不良事件等级>= 3。42%报告了严重不良事件;大多数与基础疾病相关。CHO来源的siltuximab的药代动力学特征似乎与先前的细胞系相似。无客观反应发生; 84例患者中有5例病情稳定>6周。47例患者中有33例血红蛋白升高>= 1.5 g/dL。在11和15毫克/公斤，完全持续的C-反应蛋白抑制observed.Conclusions：Siltuximab单药治疗似乎是耐受性良好，但没有临床活性的实体瘤，包括卵巢癌和KRAS突变的癌症。推荐的II期剂量为11和15 mg/kg，每3周一次。(C)2014年AACR。
Purpose: This phase I/II study evaluated safety, efficacy, and pharmacokinetics of escalating, multiple doses of siltuximab, a chimeric anti-interleukin (IL)-6 monoclonal antibody derived from a new Chinese hamster ovary (CHO) cell line in patients with advanced/refractory solid tumors.Experimental Design: In the phase I dose-escalation cohorts, 20 patients with advanced/refractory solid tumors received siltuximab 2.8 or 5.5 mg/kg every 2 weeks or 11 or 15 mg/kg every 3 weeks intravenously (i.v.). In the phase I expansion (n = 24) and phase II cohorts (n = 40), patients with Kirsten rat sarcoma-2 (KRAS)-mutant tumors, ovarian, pancreatic, or anti-EGF receptor (EGFR) refractory/resistant non-small cell lung cancer (NSCLC), colorectal, or H&N cancer received 15 mg/kg every 3 weeks. The phase II primary efficacy endpoint was complete response, partial response, or stable disease >6 weeks.Results: Eighty-four patients (35 colorectal, 29 ovarian, 9 pancreatic, and 11 other) received a median of three (range, 1-45) cycles. One dose-limiting toxicity occurred at 5.5 mg/kg. Common grade >= 3 adverse events were hepatic function abnormalities (15%), physical health deterioration (12%), and fatigue (11%). Ten percent of patients had siltuximab-related grade >= 3 adverse events. Neutropenia (4%) was the only possibly related adverse event grade >= 3 reported in >1 patient. Serious adverse events were reported in 42%; most were related to underlying disease. The pharmacokinetic profile of CHO-derived siltuximab appears similar to the previous cell line. No objective responses occurred; 5 of 84 patients had stable disease >6 weeks. Hemoglobin increased >= 1.5 g/dL in 33 of 47 patients. At 11 and 15 mg/kg, completely sustained C-reactive protein suppression was observed.Conclusions: Siltuximab monotherapy appears to be well tolerated but without clinical activity in solid tumors, including ovarian and KRAS-mutant cancers. The recommended phase II doses were 11 and 15 mg/kg every 3 weeks. (C) 2014 AACR.